The following description provides a summary of information relevant to the present disclosure and is not an admission that any of the information provided or publications referenced herein is prior art to the present disclosure.
Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) represents a significant health-care problem for South-East Asia. The incidence rate of NPC in South-East Asian males is 10 to 21.4 per 100 000 (Chang et al., Virus Res (2009) 143: 209-221). Current therapies are effective in controlling and curing non-metastasized NPC, however treatments for metastatic disease are limited. The median survival time for patients with the disseminated form of disease ranges from 11 to 22 months (Wee et al., J Clin Oncol (2005) 23: 6730-6738). An emerging alternative to chemotherapy is the use of immune-therapy strategies, which have focused on increasing the immune response to viral antigens.
Experimental immunotherapies have included dendritic cell (DC) vaccination (Gerdemann et al., Mol Ther (2009) 17: 1616-1625; Chia et al., Ann Oncol (2012) 23: 997-1005; Moosmann et al., Blood (2010) 115: 2960-2970), checkpoint inhibitor blockade (NCCT02460224; NCT02339558; Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369:134-44), cytotoxic-T-lymphocyte (CTL) infusion (Louis et al., Blood (2009) 113: 2442-2450; Straathof et al., Blood (2005) 105: 1898-1904; Louis et al., J Immunother (2010) 33: 983-990) or expansion (Smith et al., Cancer Res. (2012) 72: 1116-1125), and CAR-T therapy. The cellular strategies have the end objective of inducing a cytotoxic T-cell response that is capable of directly killing virally infected tumors. Whilst there has been great progress in the application of checkpoint inhibitor blockade against tumors, their use against NPC has been limited. Efficacy of the therapeutic PD-1 antibody, Pembrolizumab, against NPC resulted in a median progression free survival rate of 5.6 months (Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369:134-44). Furthermore, to date there has been no identification of a reliable biomarker to predict checkpoint inhibitor efficacy. CAR-T therapy has shown much promise against melanomas and lymphomas but has shown limited efficacy in clearing solid tumors. Similar to checkpoint inhibitor blockade, there has been no clear identification of factors that contribute to this failure. Identification of a series of biomarkers that could identify both how well patients will respond to therapy and when they will fail to respond would be invaluable for the healthcare community.
This lack of efficacy of CAR-T therapies against solid tumors has been hypothesized to be partially attributable to an immunosuppressive state within the tumor microenvironment. During the establishment of the tumor an immunosuppressive environment is induced, in which regulatory T cells (Treg) contribute and play a role in the maintenance of this phenotype. Treatment with the chemotherapeutic gemcitabine in a variety of murine cancer models have shown to selectively deplete the Treg population without effecting the CTL population (Suzuki et al., Clin Cancer Res (2005) 11: 6713-6721; Nowak et al., Cancer Res (2002) 62: 2353-2358; Shevchenko et al., Int J Cancer (2013) 133: 98-107). Studies of the effects of gemcitabine on the Treg compartment in humans have so far been limited but early reports are showing that treatment results in a similar contraction of the regulatory subset both in vitro (Kan et al., Anticancer Res (2012) 32: 5363-5369) and in vivo (Rettig et al., Int J Cancer (2011) 129: 832-838).
Another regulatory cell type that is of increasing interest are the myeloid-derived suppressor cells (MDSCs). MDSCs are a population of myeloid cells that are expanded in the presence of various cancers. In humans MDSCs are a heterogeneous population but can be broadly defined as HLA-DR−, CD11b+, CD33+, two subsets can be subdivided from this population as either monocytic (CD14+) or granulocytic (CD15+) (Wesolowski et al., J Immunother Cancer (2013)1:10; Dumitru et al., Cancer Immunol Immunother (2012) 61: 1155-1167; Filipazzi et al., Cancer Immunol Immunother (2011) 61: 255-263). These cells have been demonstrated to be functionally immunosuppressive but their subtype and frequency is dependent on the disease being studied. Treatment of murine cancer models with gemcitabine shows a reduction in the total number of MDSCs (Suzuki et al., Clin Cancer Res (2005) 11: 6713-6721; Ding et al., Cancer Res (2014) 74(13): 3441-3453; Huang et al., Cancer Immunol Immunother (2013) 62: 1439-1451). The role of MDSC in EBV+ NPC is poorly understood.